Citalopram is a drug which has been known for some time for the treatment of depression. Because it has a chiral center, citalopram is normally produced and marketed in the form of a racemic mixture.
The S(+) enantiomer, better known as escitalopram, is responsible for almost all of the pharmacological activity of the citalopram racemate. The preparation of citalopram is described, for example, in European patent application EP1032566 while that of its enantiomer, escitalopram, is described, for example, in European patent application EP347066, both of which are incorporated herein by reference in their entirety. Both of the above-mentioned methods provide for starting from a common intermediate, 5-cyanophthalide, whose structural formula is indicated below.

Numerous publications describe methods for the preparation of 5-cyanophthalide. One such method was originally proposed by L. F. Levy and H. Stephen, J. Chem. Soc., 867 (1931). Said method involves starting from 5-aminophthalide, which is converted into 5-cyanophthalide by means of a diazotization reaction followed by a reaction with CuCN.
Other methods have been described over the years. For example, EP1140886 describes a method for the synthesis of 5-cyanophthalide starting from 5-carboxyphthalide. The method provides for a reaction between 5-carboxyphthalide and a chlorinating agent, such as thionyl chloride. This produces the chlorocarbonyl derivative, which is then reacted with alkylamines or ammonia to give the corresponding carbamyl derivatives. When subjected to a dehydration reaction, the carbamyl derivatives give 5-cyanophthalide. The yields of 5-cyanophthalide starting from 5-carboxyphthalide reported in EP1140886 are on the order of 68%.
EP 1254129, on the other hand, provides for the synthesis of 5-cyanophthalide by reacting a thiazolyl intermediate and an oxazolidine derivative of 5-carboxyphthalide. The product is subsequently dehydrated to give cyanophthalide.
All of the methods mentioned above describe processes in which it is necessary to isolate the reaction intermediates and/or to use potentially dangerous reagents, such as ammonia or alkylamines. There remains a need in the art for methods of producing 5-cyanophthalide starting from 5-carboxyphthalide with improved yields, scalability and process safety.